ABCC9
protein-codingATP binding cassette subfamily C member 9, the group of ATP binding cassette subfamily C
Gene summary
The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MRP subfamily which is involved in multi-drug resistance. This protein is thought to form ATP-sensitive potassium channels in cardiac, skeletal, and vascular and non-vascular smooth muscle. Protein structure suggests a role as the drug-binding channel-modulating subunit of the extra-pancreatic ATP-sensitive potassium channels. Mutations in this gene are associated with cardiomyopathy dilated type 1O. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~145.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0009406
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0012062
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0015470
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0012062
Submitter: Illumina
The ABCC9 gene is located on chromosome 12 at 12p12.1 and encodes the ATP binding cassette subfamily C member 9 protein, which is a subunit of ATP-sensitive potassium channels along with KCNJ11 in cardiac and smooth muscle. The ABCC9 gene was first reported in relation to dilated cardiomyopathy in 2004 (15034580: Bienengraeber et al. 2004). Evidence supporting this gene-disease relationship includes limited case-level and experimental data. Three heterozygous variants (one frameshift, one stop-gained, and one missense) in this gene were reported in three unrelated patients (15034580: Bienengraeber et al. 2004; 24503780: Pugh et al. 2014). The mechanism of disease is unknown, but in vitro analyses of the identified variants suggested they result in partial protein mislocalization and abnormal Katp channel responses to ATP and ADP (15034580: Bienengraeber et al. 2004). ABCC9 is expressed in cardiac tissue and homozygous mice with an exon 5 deletion die prematurely and have decreased ejection fraction and cardiac fraction shortening (24648545: Fahrenbach et al. 2014). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.
Inheritance Pattern: AR
Disease ID:MONDO:0859224
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0012062
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0012062
Submitter: ClinGen
ABCC9 was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2004 (Bienengraeber et al., 2003, PMID: 15034580). ABCC9 was originally evaluated for DCM by the ClinGen DCM GCEP on 08/28/20 (SOP Version 7). Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 11/15/2024. As a result, the classification did not change. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. Human genetic evidence supporting this gene-disease relationship includes only case-level data. At least 2 variants (including 1 missense and 1 frameshift) have been reported in humans with DCM (Bienengraeber et al., 2003, PMID: 15034580). In addition, this gene-disease assertion is supported by animal models (Fahrenbach et al., 2014, PMID: 24648545 and Smeland et al., 2019, PMID: 31575858) and expression studies (Kepenek et al., 2020, PMID: 31948008). In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of ABCC9 with autosomal dominant DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 11/15/2024 (SOP Version 10).
Inheritance Pattern: AD
Disease ID:MONDO:0009406
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0859224
Submitter: PanelApp Australia
Inheritance Pattern: Unknown
Disease ID:MONDO:0013545
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0009406
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0859224
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0015263
Submitter: ClinGen
ATP-binding cassette, subfamily C, member 9 (*ABCC9*) was first reported in relation to autosomal dominant Brugada Syndrome in 2014 (Hu et al., PMID 24439875). Variation in *ABCC9* has been reported in Cantú Syndrome (ClinGen curated definitive) cases as well as non-syndromic cardiac disease cases. For the non-syndromic cardiac disease cases curated here, features of Brugada Syndrome, atrial fibrillation, early repolarization syndrome, and sudden cardiac arrest have been reported in at least seven cases. All but one of the reported variants are missense with the remaining being a short frame shifting indel. Most of the curated variants have a high population frequency in gnomAD v4.1, and what functional data that is available is not conclusive. Evidence disputing this gene-disease relationship includes case-level data and experimental data. There are two primary isoforms of the coding product, SUR2A and SUR2B. SUR2A is considered to be a primarily cardiac specific isoform; however, while it is expressed in cardiac tissue, expression is not entirely unique to the heart (PMID 8798681). In summary, the evidence supporting the relationship between *ABCC9* and autosomal dominant Brugada syndrome has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role *ABCC9* plays in this disease. This classification was approved by the ClinGen Hereditary Cardiovascular Disease GCEP on the meeting date October 28, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0009406
Submitter: ClinGen
The *ABCC9 *gene (OMIM:601439) is located on chromosome 12 at 12p12.1 and encodes a subunit of ATP-sensitive potassium channels which coassembles with KCNJ11 to form cardiac and smooth muscle-type KATP channels . KCNJ11 forms the channel pore while ABCC9 is required for activation and regulation. ABCC9 can also form a sulfonylurea-sensitive but ATP-insensitive potassium channel with KCNJ8. The *ABCC9* gene was first reported in relation to autosomal dominant Cantu syndrome in 2012 (van Bon et al. 2012, PMID:22608503). Cantu syndrome (CS, MONDO ID: 0009406) is characterized by the following symptoms: cardiomegaly, hypertrichosis, and coarse facial features. In addition, some individuals with Cantu syndrome have hyperflexibility, edema, dilated aortic root, and mild intellectual disability. There is incomplete penetrance of CS-associated features, without clear correlation to genotype. Evidence supporting this gene-disease relationship includes case-level data and experimental data. There are at least 77 individuals with Cantu syndrome reported in literature, with 29 unique variants (10 cases confirmed to be de novo), 19 of which were scored in this curation (PMID: 31828977, PMID: 39031464). The curation includes heterozygous missense variants only, predominantly in the TMD2 region of the protein (transmembrane domain 2). The variants are predicted to result in membrane hyperpolarization, through a gain-of-function mechanism in KATP channels. Supporting experimental evidence includes functional alteration in patient cells (whole-cell voltage clamp experiment), and one mouse model. Studies of the knock-in mouse models showed increased vascular smooth muscle KATP channel activity, chronic vasodilation, and cardiomegaly. The phenotype was somewhat mild even in homozygous mice, due to an alternative splicing event that does not occur in human transcripts (PMID: 33529173 Zhang et al., 2021; PMID: 31821173, McClenaghan et al. 2020; PMID: 30089727, Huang et al. 2018). In summary, there is definitive evidence to support the relationship between ABCC9 and Cantu syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date February 21st, 2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0859224
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0015263
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0016333
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0009406
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0009406
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal; Neurologic
Intervention: Cardiovascular
Rationale: Surveillance for related cardiac complications, which have been reported to include cardiomyopathy and arrhythmias, may allow early medical intervention, decreasing morbidity and mortality; Cantu syndrome, which may be clinically recognizable,can include cardiovascular malformations that would benefit from surveillance/intervention similar to other ABCC9-related disorders
Comments: Though manifestations have been described in adults, surveillance and interventions should likely begin in the pediatric period
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ABCC9 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_020297.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 21 | 489 | 4 | 514 | ||
| missense | 12 | 31 | 767 | 31 | 2 | 843 |
| nonsense | 14 | 11 | 13 | 38 | ||
| start loss | 2 | 2 | ||||
| frameshift | 27 | 9 | 20 | 56 | ||
| splice donor/acceptor (+/-2bp) | 2 | 31 | 25 | 1 | 59 | |
| Total | 55 | 82 | 848 | 521 | 6 | 1512 |
Highest pathogenic variant AF is 0.000011166544
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_064693.2 | 38 | MANE Select | |
| Ensembl | ENSP00000261200.4 | 38 | MANE Select | |
| RefSeq | NP_001364202.1 | 38 | Standard | |
| RefSeq | NP_001364203.1 | 33 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- ABC transporters - Homo sapiens (human)
- Antiarrhythmic Pathway, Pharmacodynamics
- Disopyramide Action Pathway
- Procainamide (Antiarrhythmic) Action Pathway
- Phenytoin (Antiarrhythmic) Action Pathway
Biological Process
- potassium ion transport
- response to drug
- defense response to virus
- transmembrane transport
- ATP hydrolysis coupled anion transmembrane transport
Molecular Function
- transporter activity
- potassium channel activity
- ATP binding
- sulfonylurea receptor activity
- potassium channel regulator activity
Cellular Component
- plasma membrane
- inward rectifying potassium channel
- membrane
- sarcomere
- sarcolemma
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000261200
- Coding exons
- 38
- Length
- 144002
- Individuals with no LoFs
- 125610
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 138
- Defined
- 125748
- p
- 0.000549
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.97 | 432 | 836 | 0.516 | 0.0000439 | 10136 |
| Missense (PolyPhen) | 73 | 222.86 | 0.32757 | 2745 | ||
| Synonymous | 0.00745 | 298 | 298 | 0.999 | 0.0000160 | 3023 |
| Loss of Function | 5.49 | 30 | 84.4 | 0.355 | 0.00000426 | 1009 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00046 | 0.00046 | rare |
| Ashkenazi Jewish | 0.00012 | 0.000099 | rare |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0.0020 | 0.0020 | notable |
| European (Non-Finnish) | 0.00046 | 0.00046 | rare |
| South Asian | 0.00049 | 0.00049 | rare |
| Other | 0.00082 | 0.00081 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Subunit of ATP-sensitive potassium channels (KATP). Can form cardiac and smooth muscle-type KATP channels with KCNJ11. KCNJ11 forms the channel pore while ABCC9 is required for activation and regulation. {ECO:0000269|PubMed:9831708}.;
- Disease
- DISEASE: Cardiomyopathy, dilated 1O (CMD1O) [MIM:608569]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:15034580}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Atrial fibrillation, familial, 12 (ATFB12) [MIM:614050]: A familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. {ECO:0000269|PubMed:17245405}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hypertrichotic osteochondrodysplasia (HTOCD) [MIM:239850]: A rare disorder characterized by congenital hypertrichosis, neonatal macrosomia, a distinct osteochondrodysplasia, and cardiomegaly. The hypertrichosis leads to thick scalp hair, which extends onto the forehead, and a general increase in body hair. In addition, macrocephaly and coarse facial features, including a broad nasal bridge, epicanthal folds, a wide mouth, and full lips, can be suggestive of a storage disorder. About half of affected individuals are macrosomic and edematous at birth, whereas in childhood they usually have a muscular appearance with little subcutaneous fat. Thickened calvarium, narrow thorax, wide ribs, flattened or ovoid vertebral bodies, coxa valga, osteopenia, enlarged medullary canals, and metaphyseal widening of long bones have been reported. Cardiac manifestations such as patent ductus arteriosus, ventricular hypertrophy, pulmonary hypertension, and pericardial effusions are present in approximately 80% of cases. Motor development is usually delayed due to hypotonia. Most patients have a mild speech delay, and a small percentage have learning difficulties or intellectual disability. {ECO:0000269|PubMed:22608503, ECO:0000269|PubMed:22610116, ECO:0000269|PubMed:26621776}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.157
Intolerance Scores
- LoFtool
- 0.0477
- RVIS EVS
- -1.97
- RVIS percentile EVS
- 1.82
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.762
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |